Genetics of Oxidative Stress in Ventricular Remodeling

心室重构中氧化应激的遗传学

• 批准号: 6637875
• 负责人: Vasan S Ramachandran
• 金额: $ 12.6万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637875
• 关键词: antioxidants; biomarker; blood chemistry; cardiovascular disorder epidemiology; clinical research; gene environment interaction; genetic mapping; genetic polymorphism; genetic susceptibility; heart imaging /visualization /scanning; heart ventricle; human population genetics; human subject; myocardium disorder; oxidative stress; ventricular hypertrophy

DESCRIPTION (provided by applicant): Experimental studies have established that oxidative stress is a major determinant of LV remodeling, and as a result, contributes to the development of LV dysfunction. Myocardial redox status is determined by the balance between anti and prooxidant enzymes that are under genetic control. Single nucleotide polymorphisms (SNPs) have been identified in genes for several oxidant (antioxidants: superoxide dismutases, glutathione peroxidase, catalase, paraoxonase, heme oxygenase; prooxidants: myeloperoxidases, NAD(P)H oxidases) and nitrosant (nitric oxide synthases) pathway enzymes. Some of these have been associated with altered enzymatic activity/stability, which based upon animal studies could contribute to LV remodeling. It is unclear if SNPs in genes for these enzymes are associated with alterations in oxidative stress biomarkers, or with echocardiographic (echo) indices of LV remodeling (LV dilation or hypertrophy) in humans. As part of this response to the RFA, we will measure plasma total antioxidant status (TAS), protein carbonyls, myeloperoxidase, heat shock protein 70, and urinary 3-nitrotyrosine in 1563 Framingham Heart Study (FHS) subjects. We will use existing echo, urinary isoprostane data for these subjects, and will genotype for known missense and regulatory SNPs in the genes for oxidant pathway enzymes as part of the FHS component of the NHLBI Program for Genomic Applications. We hypothesize that SNPs associated with decreased antioxidant or increased prooxidant activity will be associated with increased systemic levels of biomarkers of oxidative stress, reduced plasma TAS, and with increased LV internal dimensions and LV mass. We also postulate that biomarkers of oxidative stress will be positively associated with increased echo LV mass and internal dimensions. These hypotheses will be addressed in 3 Specific Aims: 1. Examine the relations of SNPs in oxidative pathway enzyme genes and biomarkers of oxidative stress 2. Analyze the cross-sectional relations between oxidative stress biomarkers and echo LV dimensions and LV mass. 3. Investigate the cross-sectional relations of SNPs in oxidative pathway enzyme genes to echo LV measurements. This proposal responds to the RFA by integrating genotypic and phenotypic characterization of oxidative stress, relating oxidative stress measures to echo indices of LV remodeling, using existing FHS data sets and stored biological specimens, and establishing a multidisciplinary collaboration of molecular biologists, scientists with expertise in evaluating oxidative stress, genetic and cardiovascular epidemiologists, and statisticians.

描述（由申请人提供）： 实验研究表明，氧化应激是主要的应激反应。 LV 重塑的决定因素，因此有助于发展 左室功能障碍。心肌氧化还原状态由平衡决定 受基因控制的抗氧化酶和促氧化酶之间的关系。单身的 已在多种基因中鉴定出核苷酸多态性 (SNP) 氧化剂（抗氧化剂：超氧化物歧化酶、谷胱甘肽过氧化物酶、 过氧化氢酶、对氧磷酶、血红素加氧酶；促氧化剂：髓过氧化物酶、NAD(P)H 氧化酶）和亚硝基（一氧化氮合酶）途径酶。 一些 这些与酶活性/稳定性的改变有关， 基于动物研究的结果可能有助于左心室重塑。目前还不清楚是否 这些酶基因中的 S​​NP 与氧化的改变有关 应激生物标志物，或左心室重构的超声心动图 (echo) 指数 （左心室扩张或肥大）在人类中。 作为对 RFA 回应的一部分， 我们将测量血浆总抗氧化状态（TAS）、蛋白质羰基、 1563 髓过氧化物酶、热休克蛋白 70 和尿 3-硝基酪氨酸 弗雷明汉心脏研究 (FHS) 科目。我们将利用现有的回声、尿 这些受试者的异前列烷数据，并将对已知的错义和基因型进行基因分型 作为 FHS 一部分的氧化途径酶基因中的调节 SNP NHLBI 基因组应用计划的组成部分。我们假设 与抗氧化剂降低或促氧化剂活性增加相关的 SNP 与氧化生物标志物的全身水平升高有关 应力，减少血浆 TAS，并增加 LV 内部尺寸和 LV 大量的。我们还假设氧化应激的生物标志物将呈阳性 与左心室回声质量和内部尺寸增加有关。 这些 假设将在 3 个具体目标中得到解决： 1. 检查 氧化途径酶基因中的SNP和氧化应激的生物标志物2。 分析氧化应激生物标志物与 回声 LV 尺寸和 LV 质量。 3. 研究横截面关系 氧化途径酶基因中的 S​​NP 与 LV 测量结果相呼应。 这 提案通过整合基因型和表型来回应 RFA 氧化应激的特征，将氧化应激措施与 LV 重塑的回波指数，使用现有的 FHS 数据集并存储 生物标本，并建立多学科合作 分子生物学家、具有评估氧化作用专业知识的科学家 压力、遗传和心血管流行病学家以及统计学家。